Can Plitidepsin Be Used as an Antiviral Against RSV?

Human respiratory syncytial virus (HRSV) is a main cause of acute lower respiratory tract infections in infants, the elderly and the immunocompromised patients. Although vaccines have recently been approved for the elderly and for pregnant women, there is no curative treatment for HRSV. HRSV replicates in the cytoplasm of infected cells, and transcription and replication of the viral genome depend on the viral RNA polymerase complex, which recruits cellular factors for RNA synthesis. Among them, the eucaryotic translation elongation factor 1A (eEF1A) was previously shown to be critical for HRSV replication. eEF1A activity can be inhibited by plitidepsin (Aplidin), a cyclopeptide extracted from ascidian Aplidium albicans, which was shown highly potent against SARS-CoV-2, with a 50% inhibitory concentration (IC90) of 0.70 to 1.62 nM depending on the cell line. Here, we investigated whether plitidepsin could also inhibit HRSV replication. We found that plitidepsin inhibited HRSV replication with an IC50 of {approx}3 nM in cell cultures. However, further investigation revealed that plitidepsin has pleiotropic effects, affecting the translation of both cellular and viral proteins in a similar manner. Overall, our results show that plitidepsin blocks cellular translation and indicate that plitidepsin induces a proteasome-mediated degradation of eEF1A, also showing the dependance of HRSV replication to cellular factors such as eEF1A. These results thus highlight an original mechanism of action of plitidepsin on eEF1A, which render the use of this compound for antiviral therapy very risky.